6-methyl-9alpha, 21 difluoro-11 oxygenated 17alpha hydroxy-1, 4 pregnadiene-3, 20 dione steroid compounds



United States Patent 6-METHYL-9a,21 DIFLUORO-ll OXYGENATED 17a HYDROXY-1,4 PREGNADIENE-3,20 DIONESTER- OID COMPOUNDS Frank H. Lincoln, Jr., Kalamazoo, William P. Schneider, Kalamazoo Township, Kalamazoo County, and George B. Spero, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application March 6, 1957 Serial No. 644,201

3 Claims. (Cl. 260-39745) CH! CH onion omosom o=o 'o='0 |----OH ----OH HO HO CH3 CH3 40 CH: CH:

CH: CH:

CHQF 01121 I I 46 C=0 C= ----0H L on HO HO OH: CH8

IV 111 ([113 E3 CH3 CH3 31am omF 0:0 C= CH: IN |---0H HO- OH:

I V VI CH3 CH3 ice Alternatively, the new product VIII can be made by the following sequence of steps:

({JHsOAG C=O on Q ox I o (fHaOSOaR C=O XVI (iHflF 3 VIII wherein X is a halogen of atomic number between 17 and 35, inclusive, R is an organic ra dical such as methyl, ethyl, phenyl, tolyl, n'aphthyl, or the like, with methyl preferred, and Ac is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

The process of the present invention represented by the sequence of Formulae I thru IX comprises: treating 6-methyl 11fi,l7a,-21 trihydroxy 1,4-pregnadiene-3,20- dione [1-dehydro-6-methylhydrocortisone (I)] with an organic sulfonyl halide such as methanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonyl bromide, benzenesulfonyl chloride, ozor B-naphthylsulfonyl chloride, or the like to obtain the corresponding 21 ester, a 21- alkyl or .21-arylsulfonate of G-methyl-l1p,17ot,21-trihydroxy-l,4-pregnadiene-3,ZO-dione (II); treating the thus produced 21-alkylor arylsulfonate of 6-methyl-11p3,17a,- 2l-trihydroxy-1,4-pregnadiene-3,20-dione with an alkali metal iodide, such as sodium iodide in acetone solution to obtain 6-methyl-1113,17a dihydroxy-21-iodo-1,4-pregnadiene-3,20-dione (III); treating the thus obtained 6- methyl-11fl,17u-dihydroxy 2l-iodo-1,4-pregnadiene-3,20- dione with silver fluoride, preferably in acetonitrile solution, to obtain 6-methyl-1lfl,l7a-dihydroxy-2l-fluoro- 1,4-pregnadiene-3,20-dione (IV); alternatively G-methyl 11p,17a-dihydroxy-21-fiuoro-1,4 pregnadiene 3,20-dione is obtained by treating the sulfonate (II) with potassium fluoride as shown in Example 19; dehydrating the thus obtained 6-methyl-1 1,8, 17a-dihydroxy-21-fluoro-1,4-pregnadiene-3,20-dione, for example, with sulfuric acid, thionyl chloride or preferably with an acid N-haloamide or N-haloimide and then with anhydrous sulfur dioxide to obtain the corresponding 6-methyl-17ot-hydroxy-2lfluoro-1,4,9( l1)-pregnatriene-3,20-dione (V) treating the thus obtained 6-methyl-l7a-hydroxy-2l-fluoro-1,4,9( l 1 pregnatriene-3,20-dione with a hypohalous acid such as hypochlorous or hypobromous acid preferably produced in situ by adding an N-haloacylamide or N-haloacylimide in the presence of an acid to obtain the corresponding 6-methyl-9u-halo-1 1,8,17u-dihydroxy-2l-fluoro-1,4-p1egnadiene-3,20-dione (VI); treating the thus obtained 6- methyl-9a-halo-11B,l7a-dihydroxy 21-fluoro-l,4-pregnadiene-3,20-dione with a mild base, for example, sodium or potassium acetate to obtain the corresponding 6- methyl 913,11B-oxido-17m-hydroxy- 2l-fluoro-l,4-pregnadien e-3,20-dione (VII); treating the thus obtained oxido compound VII with hydrogen fluoride to obtain 6-methyl- 9m,21-difluoro-11p,17u"- dihydroxy-1,4 pregnadiene-3,20- dione (VIII), and if desired oxidizing the thus obtained 6-methyl-9a,21 difluoro-11B,1'7a dihydroxy-1,4-pregnadione-3,20-dione with chromic anhydride or a dichromate or other oxidizing agents to obtain 6-methyl-9a,2l-difluoro-l7a-hydroxy-1,4-pregnadiene-3,1 1,20-trione (IX) In the alternative process the steps of fluorination are reversed so that first the 9a-fluoro group is introduced a into the 1-dehydro-6-rnethylhydrocortisone ester and thereupon the 21-hydroxyl group is replaced with fluorine. The process comprises the following steps: dehydrating the 6-methylhydrocortisone Zl-acylate with sulfuric acid, thionyl chloride, or preferably reacting with an acid N- haloamide or N-haloirnide and then with anhydrous sulfur dioxide, to obtain 6-rnethyl-17a,21-dihydroxy-1,4,9(ll)- pregnatriene-3,20-dione 2l-acylate (XI); treating the thus produced 6 methyl17a,2l-dihydroxy l,4,9(1l)-pregnatriene-3,20-dione 2l-acylate with a hypohalous acid such as hypochlorous acid or hypobromous acid, preferably bv producing the hypohalous acid in situ, for example, in a mixture of N-haloacylamide or N-haloacylimide in the presence of acid, to obtain the corresponding 6-methyl- 9a-halo 1l}3,17u,21 trihydroxy 1,4 pregnadiene-3,20- dione 2l-acylate (XII). Treating the thus produced 6- methyl-9a-halo-ll ,B,170c,21 trihydroxy 1,4-pregnadiene- 3,20-dione 21-acylate with a base such as anhydrous potassium acetate or anhydrous sodium acetate yields the corresponding epoxy compound, 6-methyl-9p,ll 8-oxido- 17,2l-dihydroxy-1,4-pregnadiene-3,20-dione Zl-acylate (XIII); treating the thus obtained 6-metl1yl-9;8,1l /8-oxido-- 17a,21-dihydroxy 1,4-pregnadiene-3,20 dione 2l-acylate with hydrogen fluoride yields the corresponding 6methyl- 9a fluoro-l1B,-17a,2l trihydroxy 1,4-pregnadienc-3,20- dione 2l-acylate (XIV); hydrolyzing this ester in conventional manner with a base preferably in a nitrogen atmosphere yields the triol, l-dehydro-6-methyl-9a-fluorohydrocortisone (XV). Treating the thus obtained l-dehydro- 6-methyl-9a-fluoro-hydrocortisone with an organic sulfonyl halide, such as methanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonyl bromide, benzenesulfonyl chloride, naphthylsulfonyl chloride, or the like v yields the corresponding 1-dehydro-6-methyl-9wfiuorohydrocortisone 21-organic sulfonate (XVI); treating the thus obtained sulfonate of 1-dehydro-6-methyl-9wfluorohydrocortisone with sodium iodide in acetone solution yields 6-methyl-9a-fluoro-l 1p2,17u-dihydroxy-21-iodo-l ,4- pregnadiene-3,20-dione (XVII); and treating the thus ob tained 2l-iodo compound (XVII) with excess of silver fluoride preferably in acetonitrile solution yields 6- methyl-9a,2 l-difluoro'-1 1 3, 17a-dihydroxy- 1 ,4-pregnadiene- 3,20-dione (VIII). Alternatively, treating sulfonate (XVI) with potassium fluoride as shown in Example 19 produces 6-methyl-9u,21-difluoro-1 1,3, l 7u-dihydroxy-l ,4- pregnadiene-3,20-dione (VIH).

It is an object of the instant invention to provide novel 6 -methyl- 9a,2l-difluoro-llfi,l7u dihydroxy-lA-pregnadiene3,20-dione and the keto analogue thereof, 6-m-ethyl- 9a,2l 'difiuoro-l7a hydroxy-l,4 pregnadiene --3,ll,20- trione. It is another object of the instant invention to provide methods for-the production of 6-methyl-9u,21-difiuoro-l1,8,l7ot-dihydroxy-l,4-pregnadiene-3,20-dione and 6-methyl-9a,2l difluoro-17a hydroxy-l,4 pregnadiene- 3,11,20-trione. Other objects of this invention will be apparent to those skilled in the art to which this invention pertains.

' The novel compounds 6-methyl9a,21-difluoro-1l[3,l7adihydroxy-l,4-pregnadiene-3,20-dione and 6-methyl-9a,- 2l-difluoro-l7a-hydroxy-1,4-pregnadiene 3,11,20 trione possess a high order of physiological activity and especially a high order of glucocorticoid activity which is several times that of hydrocortisone or cortisone. In addition, they are not salt retaining but have distinct diuretic qualities. The novel synthetic corticosteroid hormones of the present invention, 6-methyl-9a,2l-difluorol118,l7a-dihydroxy-1,4-pregnadiene 3,20 dione and 6- methyl-9a,21-difluoro 17cc hydroxy 1,4 pregnadiene- 3,11,20-trine, possess also strong anti-inflammatory activity and are thus useful in the management of arthritis, especially in cases where in addition to chronic congestive heart failure, nephrotic syndromes and other circulatory symptoms are present. The compounds may be given in oral compositions and tablets, illustratively, using either polyethylene glycol 4000 or 6000 as a carrier, or lactose and/or sucrose as diluent. Especially useful is the novel 6a-methyl-9a,2l-difluoro-l11S,17ot-dihydroxyl,4-pregnadiene-3,20-dione which can be also used in topical applications such as ointments, lotions, jellies, creams, suppositories, bougies, aqueous suspension etc. Examples of advantageous topical preparations are given below. While the examples below are to the 6u-methyl- 9a,21-difluoro 11fl,17oc dihydroxy 1,4 pregnadiene- 3,20-dione, equivalent amounts of 6ot-methyl-9ou2l-difluoro-17u-hydroxy-1,4-pregnadiene 3,11,20 trione, the 6fl-epimers, and other 6-lower-alkyl and 6-phenyl homologues of the compound of this invention are substitutable therein.

A dermatological and ophthalmic ointment has the following composition:

Lbs.

Wool fat, U. S. P 100 Mineral oil, U. S. P 125 6a-methyl-9a,2l-difiuoro 115,17u dihydroxy 1,4-

pregnadiene-3,20-dione (micronized) 2 White petrolatum, U. S. P 500 Incorporation of an antibiotic in the ointment, especially neomycin sulfate, has therapeutic advantages each active ingredient potentiating and supplementing the useful properties of the other. Such an ointment is as follows:

Lbs. Wool fat, U. S. P 100 Mineral oil, U. S. P 125 Neomycin sulfate 3 6ct-methyl-9a,2l-difluoro 115,170: dihydroxy 1,4-

pregnadiene-3,20-dione (micronized) 0.7 White petrolatum, U. S. P 50 In place of, or in addition to, neomycin sulfate, other antibiotics such as bacitracin, circulin, polymyxin B sulfate, gramicidin, streptomycin sulfate, dihydrostreptomycin sulfate, oxytetracycline, chlorotetracycline, tetracycline, chloramphenicol and the sulfonamides can be used in conjunction with the steroids of the present invention for preparations such as the above ointments.

In carrying out the process of the instant invention, 1-dehydro-6-alkyl- (or 6-aryl) hydrocortisone (6-alkylor 6 aryl 115,17 oc,21 trihydroxy-1,4-pregnadiene-3,20- dione) (I) is treated with an acid halide of a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aor ,B-naphthanesulfonic acid, or the like,

with methanesulfonic acid halides especially methanesul'fonyl chloride preferred. In the preferred embodiment of the instant invention the steroid is reacted with the alkylor arylsulfonyl halide in solution such as in a solvent for example pyridine, benzene, toluene, or the like at a temperature between minus ten and plus thirty degrees centigrade providing that at the lower temperature the solvent has not solidified. Pyridine is the preferred solvent, and a temperature between minus ten and plus ten degrees centigrade is preferred. The time of reaction is usually between thirty minutes and six or eight hours, after which the product, 6-alkylor 6- aryl-l 1,6,l7a,2l-trihydroxy-1,4-pregnadiene-3,20-dione 21- alkylor arylsulfonate is removed in conventional manner, for example, by evaporating the solvent until a dry residue is precipitated or by extracting the material from an aqueous solution. For extraction, solvents such as methylene chloride, chloroform, carbon tetrachloride, benzene, ether, toluene, or the like can be used. Removing the extraction solvent by distillation leaves the crude 6-alkylor 6-aryl-11,8,l7zx,21-trihydroxy-1,4-pregnadiene3,20-dione 2l-alkylor arylsulfonate (II).

For the purpose of producing the final product, it is unnecessary to purify the thus obtained 21-alkylor 21- arylsulfonate and the crude steroid sulfonate ester can be used for the production of 6-a1kylor 6-aryl-llp,l7adihydroxy-Zl:iodo-1,4-pregnadiene-3,20-dione.

The 2l-iodo compound is prepared by reacting the 2lalkylor arylsulfonate of 6-alkylor 6-aryl-ll/3,l7a,2ltrihydroxy-1,4-pregnadiene-3,20-di0ne with sodium or potassium iodide in a dialkyl ketone solution such as acetone solution. A molar excess of sodium iodide (three to twenty moles of sodium iodide per mole of steroid) is generally preferred for this reaction; and the reaction mixture containing 6-alky1- or 6-aryl-11fi,17u,21-trihydroxy-l,4-pregnadiene-3,20-dione 2l-alkylor arylsulfonate and the sodium iodide in acetone is heated to reflux for a period of three to four minutes to half an hour. The thus produced 6-alkylor 6-aryl-11B,17a-dihydroxy-Zl-iodo-l,4-pregnadiene-3,20-dione is isolated by evaporating the solvent. For the subsequent reaction it is unnecessary to carefully purify the thus obtained 6- alkylor 6-aryl-11p,l7a.-dihydroxy-2l-iodo-1,4-pregnadiene3,20-dione (III).

In order to obtain 6-alkylor 6-ary1-11'B,17e-dihydroxy- 2l-fluoro-l,4-pregnadiene-3,ZO-dione, the crude 6-alkylor 6 aryl 11B,l7ot-dihydroxy-2l-iodo-1,4-pregnadiene-3, 20-dione, dissolved in a suitable solvent such as acetonitrile, hexanes,heptanes, benzene, tertiary butyl alcohol, or the like with acetonitrile preferred, is reacted with silver fluoride. The reaction is usually carried out under exclusion of light and with stirring. The preferred form of silver fluoride used is a fifty percent aqueous silver fluoride solution rather than solid silver fluoride. The reaction is preferably carried out between forty to sixty degrees centigrade, however, lower or higher temperatures between ten and about 75 degrees centigrade are opereative. Since the silver iodide produced in the reaction forms a molecular compound withsilver fluoride, two moles of silver fluoride must be used per mole of steroid as the minimum amount necessary for theoretical recovery. However, it is preferred to use an even greater amount, between ten to fifty percent over and above the calculated amount, in order to obtain higher yields. The silver fluoride is generally added in portions over a period of time, the reaction time ranging usually from one-half to six hours. In order to isolate the product, thesolvent is evaporated and the crude product 6-alkylor 6-aryl- 11,8,17a-dihydroxy-21-fluoro-1,4-pregnadiene-3,20 dione (IV) extracted with a suitable solvent such as chloroform, methylene chloride, carbon tetrachloride, benzene, or the like. Purification is made by conventional procedures such as additional extraction to eliminate impurities, recrystallization or chromatography, as deemed necessary.

The thus obtained 6-alkylor 6-aryl-1l B,l7a-dihydroxy- 21-fluoro-1,4-pregnadiene-3,20-dione is dehydrated to the corresponding 6-alkyl-or 6-aryl-2l-fluoro-17a-hydroxyl,4,9,(11)-pregnatriene-3,20-dione by methods known in the art, for example, by dehydrating agents such as phosphorus oxychloride, hydrochloric acid or sulfuric acid and acetic acid, thionyl chloride, by pyrolysis as shown by U. S. Patents 2,640,838 and 2,640,839, and the like. In the preferred embodiment of the present invention the dehydration is effected by reacting the 11 fi-hydroxy compound with an acid N-haloamide or N-haloimide in an organic base and treating the thus produced intermediate ll-hypohalite with dry sulfur dioxide in an organic base. As reagents for the production of an ll-hypohalite, the acid N-haloamide or N-haloimide are used wherein the halogen has an atomic number from 17 to 53, inclusive,

preferably chlorine or bromine. Examples of such corn- 7 pounds are N-chloroacetarnide, N-bromoacetarnide, N- chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 3-bromo 5,5 dimethylhydantoin. Ordinarily an amount in excess of a molar equivalent, calculated on the starting llfl-hydroxy steroid, is employed. The base employed in the production of the ll-hypohalite are tertiary amines wherein the amino nitrogen is a member of an aromatic ring, for example, the pyridines, that is,

pyridine, alkyl-pyridines, piccoline, lutidine, collidine, conyrine, parvuline, or the like, or lower fatty amides such as formamide, methylformamide and dimethylformamide. The base is preferably employed in a large molar excess, calculated on the starting ll B-hydroxy steroid, for example, ten molar equivalents, and is preferably the sole reaction solvent. The reaction to produce an 11-hypohalite is generally conducted under anhydrous conditions preferably containing less than 0.1 molar equivalent of water calculated per mole of steroid. Large proportions of water decrease the yield. The temperature of the reaction is between minus forty and plus seventy degrees centigrade, the lower limit being determined by the solubility of the reaction and by the character of the solvents, and the upper limit being determined by the amount of side reaction which normally accompanies the reaction involving any halo compounds at higher temperatures. Ordinarily, room temperature (twenty to thirty degrees centigrade) is preferred for convenience and because of the consistently high yields of the desired product which are obtained at this temperature. A reaction period between five minutes to three hours is usually employed, at higher temperatures-above thirty degrees centrigrade-short reaction times are suflicient to produce completeness of the reaction.

' The thus produced 6-alkylor 6-aryl-l1fl,l7a-dihydroxy-21-fluoro-l ,4-pregnadiene-3,ZO-dione llfi-hypohalite is then treated with anhydrous sulfur dioxide in the presence of an organic base as described hereinbefore. The anhydrous sulfur dioxide;can be in the form .of gaseous or liquid sulfur dioxide or in the form of a material which in situ produces sulfur dioxide, for example, alkali metal hyposulfite. The reaction temperature ranges substantially within minus forty and plus seventy degrees centigrade and is preferably room temperature (about twenty to thirty degrees centigrade). The thus obtained product, 6-alkylor 6-aryl-l7ot-hydroxy-21-fluoro-'l,4,9- (l1)-pregnatriene-3,20-dione is isolated from the reaction mixture by conventional means such as extraction after the reaction mixture has been poured into excess of water. Organic water-immiscible solvents such as ether, chloroform, methylene chloride, carbon tetrachloride, ethyl acetate, benzene, hexanes, or the like, are used for the extraction. The thus obtained extracts are conveniently washed, dried and thereupon evaporated to give the crude 6-alkylor 6-aryl-l7a-hydroxy-2l-fiuoro-1,4,9(11)pregnatriene-3,20-dione (V) which is purified byconventional means such as recrystallization or chromatography, as deemed necessary.

pound through filtration.

. The thus produced 6-a1kylor 6-ary1-17a-hydroxy-2L fluoro-1,4,9(11)-pregnatriene-3,20-dione is converted to 6-alkylor 6-aryl-9u-halo-11[3,17a-dihydroxy-2l-fluoro-l, 4-pregnatriene-3,20-dione by adding a hypohalous acid such as hypochlorous or hypobromous acid. The hypoa halous acid is usually added by reacting an N-halo acid amide or an N-halo acid imide with an acid to produce the hypohalous acid in situ. In the preferred embodiment of the invention, the steroid, a 6-alkylor 6-aryll7a-hydroxy-21-fluoro-1,4,9( l1) pregnatriene-3,20-dionc is dissolved in an organic solvent such as methylene chloride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol, or the like, and reacted at room temperature with the hypobromous or hypochlorous acid releasing agent in the presence of an acid. Such hypohalous acid releasing agents include the N-bromoacetamide, the N- chloroacetamide, the N-brornosuccinimide, or the like, in the presence of water and an acid such as perchloric acid, dilute sulfuric acid, or the like. The reaction is usually carried out at room temperature, between fifteen to thirty degrees centigrade. However, lower or higher temperatures are operative for the process. halous acid releasing agent is generally used in one molar or slightly increased, for example, 25 percent increased amounts compared to mole of steroid. A large excess of the hypohalous acid releasing agent, while operative, is undesirable since the excess of hypohalous acid hasa tendency to react on other positions of the molecule. The reaction period is rather short and may vary between about four to five minutes to one hour. At the end of the reaction time excess of hypohalous acid is destroyed by the addition of sodium sulfite or other sulfites or hydrosulfites. The thus produced product, a 6-alkylor 6- aryl-9oc-halo-l l [3,170t-dihYd10XY 21 fluoro 1,4 pregnadiene-3,20-dione (VI), wherein the halogen atom is of atomic weight between 33 and eighty (atomic number 17 to 35), is isolated from the reaction mixture by adding excess of water and extracting the compound with or-. ganic solvents or by recovering the precipitated com- The crude product thus ob tained may be recrystallized from organic solvents, such as acetone, Skellysolve B hexane hydrocarbons, or, the like to give pure 6-alkylor 6-aryl-9a-halo-1lfl,l7a-dihydroxy-2 1 -fluorol ,4-pregnadiene-3 ,20-dione.

Oxidizing the 6-alkylor 6-aryl-9a-halo-llfl,l7a-dihy droxy-21-fluoro-l,4-pregnadiene-3,20-dione with chromic acid produces the corresponding pharmaceutically active 6-alkylor 6-aryl-9a-halo-17a-hydroxy-21-fluoro-l,4-pregnadiene-3 ,l1,20-trione.

In order to obtain the 9a-fiuoro compounds, the 9/8, 11,8-epoxy intermediates of the before-mentioned com: pounds, 6-alkylor 6-aryl-9fi,1lfl-oxido-lh-hydroxy-Zl fluoro-1,4-pregnadiene-3,20-dione are prepared. in carrying out this reaction a 6-alkylor 6-aryl-9a-halo-lle,17e dihydroxy-21-fluoro-1,4-pregnadiene-3,ZO-dione is heated in solution with a mild base. The bases useful for the cyclization include anhydrous potassium acetate, sodium bicarbonate, sodium acetate, or the like, with potassium acetate preferred. Solvents such as methanol, ethanol, acetone, tertiary butyl alcohol, or the like, can be used. The reaction time is between one-half hour and 24 hours; generally a period between three and twelve hours is suificient. The thus obtained 6-alkylor 6-aryl-9B,ll 3- oxido-17a-hydroxy-2l-fluoro-l,4-pregnadiene-3,2O dione is isolated from the reaction mixture by diluting the reac-- tion mixture with excess water and filtering the product when crystalline, or by extracting with methylene chloride or other water-immiscible solvents such as ether, Skellysolve B hexanes, pentanes, benzene, ethyl acetate, chloroform, carbon tetrachloride, or the like. Evaporation of the solvent of the extracts produces the 6-alkylor 6- aryl-9;3,1 lB-oxido-l7a-hydroxy-21-fiuoro-1,4-pregnadiene 3,20-dione (VII).

The thus obtained 6-alkylor 6-aryl-9fl,llfi-oxido-l7or-, hydroxy-21-fiuoro-1,4-pregnadiene 3,20 dione is there- The hypo upon reacted with hydrofluoric, acid. As solvents for this reaction, methylene chloride, tetrahydrofuran, ethylene dichloride, chloroform, carbon tetrachloride, or'the like are useful, with methylene chloride and tetrahydrofuran preferred. The reaction is carried out preferably with stirring at room temperature (twenty to thirty degrees centigrade) when methylene chloride is used as solvent, and at low temperatures, zero to minus eight-y degrees centigrade when tetrahydrofuran is used. With methylene chloride at room temperature aqueous (48%) hydrofluoric acid is generally used, while with tetrahydrofuran at low temperatures liquid hydrogen fluoride is used. The period of reaction is from one to 24 hours with a period from one to twelve hours usually sufficient. After the reaction is terminated, the mixture -is=poured into water and neutralized with a dilute base such as sodium bicarbonate, potassium bicarbonate, or the like. Excess of strong bases can also be used. The reaction mixture is then extracted with a water-immiscible solvent such as methylene chloride, the organic layer is separated from the water mixture, washed with water, dried and evaporated to give the crude -6-alkylor 6-aryl-9a,21-difluoro- 11,B,17ct-dihydroxy 1,4 pregnadiene 3,20 dione (VII). The thus obtained crude compound can be purified through recrystallization or chromatography.

Oxidation of 6-alkylor 6-aryl-9m,21difluoro-116,17udihydroxy-l,4-pregnadiene 3,20 dione in conventional manner, for example, with chromic anhydride or an alkali chromate, in solution such as in acetic acid, at temperatures between zero and forty degrees, provides the corresponding 6-alkylor 6-aryl-9a,21-difluoro-17a-hydroxy-1,4-pregnadiene-3 ,11,20-trione.

In the alternative procedure shown as steps X to XVII to compound VIII, the reactions involved are the same as those described before in the steps from compound I to VIII, except that the introduction of the .90t-flUOYO atom is made first, before the introduction of the 21-flu0ro atom. As starting material in this sequence, instead of the 1-dehydro-6-methylhydrocortisone, an ester thereof is used such as an acetate, propionate, butyrate, pentanoate, hexanoate, benzoate, phenylacetate, or the like, of l-dehydro-6-methylhydrocortisone. These esters (Formula X), prepared by the usual methods of esterification such as reacting 1-dehydro-6-methylhydrocortisone with an acid chloride, an acid bromide or an acid anhydride of a hydrocarbon carboxylic acid in pyridine are dehydrated in the same manner as shown for compound IV to give 6-methyll 7tx-hydroxy-2 l -acyloxy- 1 ,4,9 1 1 -pregnatriene- 3,20-dione (IX). This compound'(XI) is submitted to the same steps as shown in the sequence V through VIII before, to give 6-n1ethyl-9a-fluoro-11/3,l7a,21-trihydroxy- 1,4-pregnadiene-3,ZO-dione ZI-acylate (XIV) which is submitted to hydrolysis in known manner, that is, with a base preferably in a nitrogen atmosphere to give the free triol, 6-methyl-9cz fluoro 115,170 21 trihydroxy 1,4- pregnadiene-3,20-dione (XV).

Compound XV, 6-methyl-9wfluoro-11fl,17c,2l-trihydroxy-1,4-pregnadiene-3,ZO-dione, is thensubject to the same treatment as compound I in the sequence IIV, i. e., esterification with an arylor alkylsulfonate to give XVI, treating the thus obtained 2l-arylor alkylsulfonate of 6- methyl-9a-fluoro-1 1B,17a,21 trihydroxy-1,4-pregnadiene- 3,20-dione XVI with sodium iodide in acetone solution to give XVII and thereupon the thus obtained 21-iodo compound XVII with silver fluoride to give the product of the first procedure, i. e., 6-methyl-9a,21-difluoro-1113, 17a-dihydroxy-1,4-pregnadiene-3,20-dione (VIII). Alternatively, as shown in Example 19, compound VIII can be obtained by treating the sulfonate XVI with potassium fluoride.

The following examples are illustrative for the processes and products of the present invention, but are not to be construed as limiting.

- -EXAMPLE ,1 6a methyl 11 63170: 21 trihydroxy -1,4 pregnadiene' 3,20 dione 21 methane'sulfonate (1 dehydro -611- methylhydrocortisone 21 -methanesulfonate) A solution was prepared containing 164 milligrams (0.437 millimole) of 1-dehydro-6a-methylhydrocortisone [G. B. Spero et al., J. Am. Chem. Soc. 78, 6213 (1956)] in one milliliter of pyridine. This solution was cooled to zero degrees centigrade and treated with a cooled solution of 75 milligrams of methanesulfonyl chloride in 0.5 milliliter of pyridine. Thereafter the solution was allowed to stand at a temperature between zero and five degrees centigrade for a period of two hours. Thereafter ice and suflicient dilute hydrochloric acid to neutralize the pyridine was added and the mixture extracted with three 25-milliliter portions of methylene chloride. The extracts were combined, washed with cold sodium bicarbonate solution, then water and finally dried over anhydroussodium sulfate and evaporated at reduced pressure to give crystalline Got-methyl-11B,17a,21-trihydroxya 1,4-pregnadiene-3,ZO-dione 21 methanesulfonate.

EXAMPLE 2 6oz methyl 11,61,170: dihydroxy 2 1 iodo 1,4 pregnadiene-3,20-dione The crystalline methanesulfonate of 6a-methyl-1lfi,17a, 21-trihydroxy-1,4 pregnadiene-3,20-dione of Example 1, was dissolved in fifteen milliliters of'acetone and treated with a solution of 200 milligrams of sodium iodide in five milliliters of acetone. The mixture was heated under reflux with stirring for a period of fifteen minutes. The heating was then discontinued and the mixture concentrated to dryness at reduced pressure to give 60:- methyl 115,170 dihydroxy 21 iodo 1,4 pregnadiene-3,20-dione.

EXAMPLE 3 60a methyl 11,8,17a dihydroxy 21 fluoro 1,4 preg nadiene-3,20-dione A solution of one gram of 6a-methyl-11B,17a-dihydroxy-21-iodo-1,4-pregnadiene 3,20-dione in 150 milliliters of acetonitrile (practical grade) was prepared by heating to the boiling point. After cooling to forty degrees centigrade thesolution was protected from light and 0.8 milliliter of fifty percent aqueous solution of silver fluoride was added under stirring. The solution became cloudy and brown colored. Under continued stirring at a temperature between forty to 45 degrees centigrade, additional silver fluoride solution was added as two 0.7-milliliter portions, one hour apart. Heating and stirring was then continued for a period of two hours. The brown mixture was thereupon filtered through a bed of Celite diatomaceous earth and the filtrate evaporated at reduced pressure from a bath at a temperature of fifty degrees centigrade. The brown residue was thoroughly extracted with two one hundred-milliliter portionsof warm methylene chloride, the methylene chloride extracts concentrated to-approximately IOU-milliliter volumes and chromatographed over fifty grams of Florisil synthetic magnesium silicate. Fractions of 200 milliliters was taken as follows:

Fractions Solvent Hexane-acetone 93:7. Hexane-acetone :10.

Acetone.

The hexane mixture used was Skellysolve B 'hexanes.

Fractions 18 to 25 were combined and evaporated to give 3,20-dione,

1 1 from acetone-Skellysolve B yielded 343 milligrams of 6amethyl 115,171: dihydroxy 21 fluoro 1,4 pregnadiene3,20-dione of melting point 216 to 222'degrees Centigrade. I

Analysis.Calcd. for C H O F: C, 70.18; H, 7.76; F, 5.05. Found: C, 70.43; H, 7.91; F, 3.78.

EXAMPLE 4 6a methyl 17oz hydroxy 21 fluoro 1,4 pregnadiene-3,11,20-trione A mixture was prepared containing 0.3 gram of 60amethyl 115,170: dihydroxy 21 fluoro 1,4 pregnadiene-3,20-dione, 100 milligrams of chromic anhydride, ten milliliters of glacial acetic acid and one-half milliliter of water. This mixture was stirred and maintained at room temperature for eight hours. Thereafter the mixture was poured into fifty milliliters of ice water, neutralized by the addition of dilute sodium hydroxide and the thus obtained'precipitate collected on a filter and recrystallized three times from ethyl acetate and Skellysolve B hexanes to give 6a-methyl-17a-hydroxy-2l-fiuoro-1,4- pregnadiene-3,1 1,20-trione. v

In the same manner shown in Example 1, treating other 1-dehydro-6a-alkylhydrocortisones with the chlorides or bromides of toluenesulfonic acid, methanesulfonic acid and other organic sulfonic acids, gives the corresponding 21-toluenesulfonate or, respectively, the 2l-methanesulfonate, or the like, of the corresponding 1- dehydro-6a-alkylhydrocortisones wherein the alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or an aryl such as phenyl, or the like.

Treating the thus obtained 21-toluenesulfonate, 21- methanesulfonate or other 21-alkylor 2l-arylsulfonates of 1-dehydro-6a-alkylor l-dehydro-6-arylhydrocortisone with sodium or potassium iodide in acetone at elevated temperature, usually reflux temperature, yields the cor responding 21-iodo compound such as, for example, 6aethyl 11,8,170: dihydroxy 21 iodo 1,4 pregnadiene- 6oz propyl 115,170 dihydroxy 21 iodo- 1,4 pregnadiene 3,20 dione, 6a isopropyl 11B,l7ocdihydroxy 21 iodo 1,4 pregnadiene 3,20 dione, 6a butyl 11B,17a dihydroxy 21 iodo 1,4 pregnadiene 3,20 dione, 60c isobutyl 115,170 dihydroxy- 21 iodo 1,4 pregnadiene 3,20 dione, 60c pentyl- 115,170: dihydroxy 21 iodo 1,4 pregnadiene 3,20- dione, 60c hexyl 115,17a dihydroxy 21' iodo 1,4-

pregnadiene 3,20 dione, 6a phenyl 11,3,17ot di- 7 hydroxy 21-- iodo 1,4 pregnadiene 3,20 dione, and the like.

Treating as shown in Example 3 at reflux temperature the thus prepared 21-iodo compounds in acetonitrile with aqueous silver fluoride yields the corresponding 21- fluoro compound such as: 6a-ethyl-11,8,17u-dihydr0xy- 21 fluoro 1,4 pregnadiene 3,20 dione, 60c propyl- 11 8,17 dihydroxy 21 -fluoro 1,4 pregnadiene 3,20- dione, 60c isopropyl 11,53,170: dihydroxy 21 fluoro- 1,4 pregnadiene 3,20 dione, 6a butyl 115,170: dihydroxy 21 -fluoro 1,4 pregnadiene 3,20 dione, 6a isobutyl 11,8,17a dihydroxy 21 fluoro 1,4- pregnadiene 3,20 dione, 6a pentyl 11,8,17tz dihydroxy 21 fluoro 1,4 pregnadiene 3,20 dione, 6a hexyl 115,170: dihydroxy 21 fluoro 1,4 pregnadiene 3,20 dione, 60c phenyl 11 3,17 dihydroxy- 2l-fiuoro-l,4-pregnadiene-3,20-dione, and the like.

Instead of the l-dehydro-6a-methylhydrocortisone the 6 3-epimers can be used in the above examples and if the conditions are kept near neutral, the 6fi-epimers, such as 6;? methyl l1;3,l7u dihydroxy 21 fluoro 1,4 pregnadiene-3,20-dione can be isolated from the reaction mixture. epimers by treatment with acid or base in an organic solvent, e. g., ethanol at room temperature.

The thus obtained 65-epimers yield the 604- EXAMPLE 5 I V 6 a-methyl-1 7a-hydroxy-21-flu0ro-1,4,9 (1 1 -pregnatriene- 3,20-dime A mixture of one gram of 6a-methyl-1 113,17a-dihY- droxy-2l-fluoro-1,4-pregnadiene-3,20-dione, 650 milli grams of N-bromoacetamide and six milliliters of pyridine were stirred in the dark for a period. of thirty minutes. The mixture was cooled in an ice-water bath and a stream of sulfur dioxide was directed onto the surface of the stirred mixture until a negative potassium iodidestarch test was obtained. Fifty milliliters of water was then added to the mixture and the mixture was maintained at about five degrees centigrade for thirty minutes. The precipitated white solid was filtered, washed with water and dried under vacuum. After crystallization from acetone there was obtained about 0.7 gram of 6amethyl 17a hydroxy --21 fluoro 1,4,9(ll) pregnatriene-3,20-dione.

A solution was prepared containing 0.5 gram of 6amethyl 17oz hydroxy 21 fluoro 1,4,9(1l) pregnatriene-3,20-dione in twenty milliliters of methylene chloride and thereto was added a solution of one milliliter of 71 percent perchloric acid in ten milliliters of water and 200 milligrams of N-bromoacetamide in fifty milliliters of tertiary butyl alcohol. The mixture was maintained at room temperature for fifteen minutes and then mixed with a solution of 0.3 gram of sodium sulfite in twelve milliliters of water. The mixture was distilled at reduced pressure until the residual solution became cloudy. The product was then precipitated by the addition of milliliters of a mixture of ice-water. The white crystalline precipitate was filtered, washed with water and then dried and recrystallized from a mixture of acetone and Skellysolve B hexane hydrocarbons to give 6oz methyl 9a bromo 1113,17oc dihydroxy 2 l-fiuoro-1,4-pregnadiene-3 ,20-dione.

EXAMPLE 7 A mixture of 0.45 gram of 6a-methyl9 x-bromo- 1lB,17oc dihydroxy 21 fluoro 1,4 pregnadiene 3,20-dione, 0.45 gram of anhydrous potassium acetate and twenty milliliters of acetone was heated at its re fluxing temperature for a period of five hours. The mixture was then cooled and poured into water and extracted with methylene chloride. The methylene chloride extract was dried and poured over a column of 25 grams of Florisil synthetic magnesium silicate. The column was developed with Skellysolve B hexane hydrocarbons containing increasing portions of acetone. The Skellysolve B plus ten percent acetone eluate contained 6wmethyl- 9(11) oxido 17a hydroxy 21 fluoro 1,4 pregnadiene-3,20-dione.

EXAMPLE 8 A solution of one gram of 6a-methyl-9(ll)-oxido-17 xhydroxy-2l-fluoro-1,4-pregnadiene-3,20-dione was dis solved in fifty milliliters of methylene chlorideand there to was added five milliliters of 48 percent hydrofluoric acid and 0.5 milliliter of 71 percent perchloric acid. The mixture was stirred vigorously for six hours at room temperature and then poured into an excess of cold aqueous five percent sodium bicarbonate solution. The methylene chloride layer was separated, dried with anhydrous sodium sulfate, and then poured over a column of 100 grams of Florisil synthetic magnesium silicate. The column was developed with Skellysolve B hexanes and acetone, the fractions containing ten percent acetone aeazcse .13 were recrystallized from acetone and Skellysolve B hexanes to give pure 6a-methyl-9a,2l-difluoro-l1fl,17a-dihydroxy-1,4-pregnadiene-3,ZO-dione of melting point 262 to 274 degrees centigrade with decomposition and rotation [th, plus 71 degrees in acetone.

Analysis.Calcd. for (1 1 1 0 1 F, 9.63; Found: F, 9.80.

Following the procedure described in Examples 5 thru 8, butsubstituting other 6a-alkyl 11B,.17 dihydroxy-21- fiuoro-1,4-pregnadiene-3,20-diones for the 6a methyl- 11,8,17a dihydroxy 21 fluoro 1,4 pregnadiene 3,20-dione wherein the alkyl radical is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or an aryl radical such as phenyl, or the like, results in the corresponding 6a. alkyl 90,2l difluoro 11,8,l7a dihydroxy 1,4 pregnadiene-3,20-dione wherein the alkyl group will be ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or an aryl such as phenyl, or the like.

EXAMPLE 9 Oxidizing in the manner given in Example 4, 6a- ,methyl 911,21 difluoro 11,8,171: dihydroxy 1,4 pregnadiene-3,20-dione with chromic anhydride in acetic acid solution produces 6a-methyl-9u,21-difluoro 17a-hydroxy-l,4-pregnadiene-3,l1,20-trione.

In the manner similar to Example 9, oxidizing with chromic anhydride in acetic acid solution other 6a-alkyl- 911,21 difluoro 115,17zx dihydroxy 1,4 pregnadiene 3,20-diones results in the corresponding 6a-a1kyl-9 x,2ldifluoro 17a hydroxy 1,4 pregnadiene 3,11,20 triones-wherein the alkyl group is ethyl, propyl,'isopropyl, butyl isobutyl, pentyl, hexyl, or an aryl, such as phenyl, or the like.

EXAMPLE l0 6a-methyl-1 7oc,21-dihydr0xy-1,4,9(11)-pregnatriel1e= 3,20-dione 21 -acetate To a solution of 530 milligrams of 6u-methyl-'l1;8,l7a, 21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate (1- dehydro-6a-methylhydrocortisone 21-acetate) in five milliliters of pyridine, in an atmosphere of nitrogen, was added 225 milligrams of N-bromoacetamide. After standing at room temperature under nitrogen .forla period of thirty minutes, the reaction solution was cooled to ten to fifteen degrees centigrade and, with shaking, sulfur dioxide gas was passed over the surface until the'solution gave no color with acidified starch-iodine paper. During the addition of sulfur dioxide gas, the reaction became warm. The temperature vwas kept under thirty degrees centigrade by external cooling and by varying the rate-of sulfur dioxide addition. After standing at room temperature for a period of fifteen minutes, the reaction mixture was poured into thirty milliliters of ice water and theresulting gummy precipitate extracted with fifty milliliters of ether. The ether extract was washed with five percent hydrochloric acid solution .and water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 371 milligrams of material. This material was recrystallized from acetone-Skellysolve B hexanes to give 318 milligrams of 6u-methyl-l7a,21-dihydroXy-1,4,9(I'D-pregnatriene-3,20-dione 21-acetate of melting point 188 to 191.5 degrees centigrade.

EXAMPLE 11 6a methyl -90 bromo 11,8,17u,21 trihydroxy 1,4- pregnadiene 3,20 dione 21 acetate (1 dehydro 60cmethyl-9a-br0m0hydr0c0rtis0ne 21 -acetate) To a solution of 332 milligrams of 60c-m6thyll7oc,2l dihydroxy-1,4,9 l 1)-pregnatriene-3,20-dione 21-acetate in five milliliters of methylene chloride and 9.9 milliliters of tertiary butyl alcohol was added a-solution of 0.83 milliliter of 72 percent perchloric acid in 5.8 milliliters of water followed .by a solution of 142 milligrams of N- bromoacetamide in., 2.5 milliliters of tertiary butyl ah cohol. After stirring the reaction mixture ,for fifteen minutes, a solution f 142 milligrams of sodium sulfite in seven milliliters of water was added and the reaction mixture was concentratedto ,a volume of about 25 milliliters under reduced pressure at about sixty degrees centigrade. At this point crystallization started. The concentrate was cooled in an ice bath while stirring and 35 milliliters of water was added. After stirring for a period of twenty minutes, the crystalline product was isolated by filtration,, the crystals were washed with'water and air-dried to give .406 milligrams of 6cc-methYl-9abromo..- ,1 1,6,17a,21-trihydroxy-1,4-pregnadiene 3 ,ZO-dione 21-acetate 1-dehydro 6u methyl-9a-bromohydrocortisone ZI-acetate) of. melting point .l73qto 177 degrees centigrade (with decomposition).

EXAMPLE 12 To a solution ofi4Q6 milligrams of, 6,a-methyl-9u-bromo- 1 1e, 1 706,217llilhYd-IOXY 1 ,4-pregnadiene- 3,ZO-dione ;21-ac.etate in fifteen milliliters of acetonewas added 406 milligrams of potassium acetateand the resulting suspension was heated under reflux fora period of eighteen hours. The mixture :was then concentrated to five milliliters of volumeon the steam bath and theIQUP H ten milliliters of water was added. This caused the potassium acetate to go into solution andthe steroidal product to crystallize out. The product was separated by filtration and recrystallized from acetone to give in two crops 232 milligrams of .6ct-methyl-9fiL11B-oxido l7u,2l-dihydroxy 1,4- pregnadiene-3,20-dione ZI-acetate ofnmelting -point 255 to 263 degrees centigrade.

EXAMPLE 13 6a methyl 9a .fluoro 115,] 711,21 trihydroxy 1,4- pregnadiene 3,20 dione 21 acetate 1 dehydra- 6amethyl-9a-flu0r0hydr0c0rtis0ne Z1 -acetate) To a solution of 230 milligrams of .6a-methyl-9fl,'1113- oXido-17a,2l-dihydroxyd,4-pregnadiene-3,20-dione 21-acetate in five milliliters of methylene chloride was added 1.2 milliliters of 48 percent solution of hydrogen fluoride. The two-phase mixture wasstirred for a period of twenty hours, then diluted with fifteen milliliters of methylene chloride and carefully poured into forty milliliters of water containing four grams of sodium bicarbonate. After shaking to neutralize the excess hydrogen fluoride, the methylene chloride was separated and the water phase was extracted with more methylene chloride. The combined methylene chloride solution (about 75 milliliters) was dried over anhydrous sodium sulfate, diluted with 25 milliliters of ether and chromatographed .over twenty grams of Florisil synthetic magnesium silicate. The column was eluted as follows:

TAB LE I Fraction No. Solvent 1 milliliters) Methylene,chloride-ether(3:1).

2-6 (40 milliliters each) Skellysolve B hexaneacctone (12%). 7-16 (40 milliliters each) Skellysolve B hcxane+acetone (15%). 17-21 (40 milliliters each). Skellysolve B hexane acetone (20%). 22-28 (40 milliliters each) Skellysolvc B hcXane-Pacetone (25%). 2730 (40 milliliters each) Skellysolvc B hexancTacetone (50%).

15 3430 crnr 21-acetoxy-20-keto, 1735, 1717 emfconjugated 3-keto group, 1658 cm. ,A -double bonds, 1615, 1610 cm.- acetate C-O-bond, 1270, 1239 cmr' EXAMPLE 14 6oz-methyl-9a-flu0r0-17a,2J-dihydr0xy 1,4 pregnadiene- 3,11,20-trione 21-acetate (1 -dehydro 6a methyl 9ozfluorocortisone 21 -acetate) A solution was prepared containing in one milliliter of acetic acid fifty milligrams of 6a-methyl-9a-fiuoro-11/3, 170:,2l-trihydroxy-l,4-pregnadiene-3,20-dione 21-acetate, twenty milligrams of chromic anhydride and one drop (approximately fifty milligrams) of water. This mixture 'was shaken several times at room temperature and al lowed to stand for four hours. Thereafter it was poured into ten milliliters of water and refrigerated for twenty hours at about five degrees centigrade. The steroid which separated from theaqueous mixture was collected v on filter paper and recrystallized two times from acetone to give 6oc-methyl-9a-fluoro-17a,21-dihydroxy-1,4-pregnadiene-3,11,20-trione 21-acetate (1-dehydro-6a-methyl-9ufluorocortisone 21-acetate) In the same manner as given in Examples 10 through 14, but using as starting material the corresponding 6,6-

isomers in the sequence illustrated in particular by Examples 1 through 5, are obtained 6fi-methyl-9oc-fiuoro- 11,8,l7a,2l-trihydroxy-1,4-pregnadiene-3 ,20-dione 2 1-acetate and 6fi-methyl-9a-fluoro-17u,2l-dihydroxy-l,4-pregnadiene-3,1l,20-trione 2l-acetate. Using instead of the acetates, other esters as starting materials in the series exemplified by Examples 10 through 14, such as pro- 'butyl isobutyL'pentyl, hexyl, and the aryl group can be phenyl, benzyl, or the like.

EXAMPLE To a solution of 1.028 grams of 6a-methyl-9u-fluoro- 1.l 8,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate in 100 milliliters of methanol through which nitrogen had been bubbled for a period of ten minutes was added a solution of 1.028 grams of potassium bicarbonate in five milliliters of water which had likewise been treated with nitrogen. The resulting cloudy solution was allowed to be stirred for a period of sixteen hours at room temperature (about 25 degrees centigrade) and was then made acidic with 0.6 milliliter of acetic acid in thirty milliliters of water. The reaction mixture was then concentrated under reduced pressure at sixty degrees centigrade to a volume of twenty milliliters. A jell formed and was extracted with three 100-milliliter fractions of ethyl acetate. The combined extract was washed with dilute.so dium bicarbonate solution, and water and Was then dried and evaporated to dryness to give 0.898 gram of the free alcohol, 6a-methyl-9a-fluoro-l1fi,l7a,21-trihydroxy-1,4-pregnadiene-3,ZO-dione which recrystallized from acetone melted at 248 to 255 degrees centigrade with decomposition and had a rotation [04],; of plus 93 degrees in dioxane.

Analysis.- Calcd. for C22H2905F1 C, 1 4.84. Found: C, 67.48; H, 7.61; F, 5.02.

EXAMPLE 16 6 a-methyI-Qa-fluOrO-I 1 [3,] 711,21 -trz'hydr0xy-1 ,4- pregnadi ene-3 ,2 O-d ione 21 -methanesulf0nate To a solution of 210 milligrams of 6a-methyl-9a-fluoro- 11,8,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione in ten milliliters of pyridine, cooled to zero to five degrees centigrade, was added 0.2 milliliter of methanesulfonyl chloride. The reaction mixture was stirred at six degrees centigrade for a period of seventeen hours, thereafter diluted with two milliliters of water and then poured into forty milliliters of cold five percent aqueous hydrochloric acid solution. The resulting solid methanesulfonate was filtered, washed with water and dried to give 0.195 gram of crude 6a-methyl-9a-fluoro-11,6,17a,21-trihydroxy-l,4- pregnadiene-3,20-dione ZI-methanesulfonate of melting point 205 to 220 degrees centigrade with decomposition.

EXAMPLE 17 150 milligrams of crude 6u-methyl-9u-fluoro-115,1711, ZI-trihydroxy-1,4-pregnadiene-3 ,20-dione 21-meth anesulfonate was dissolvedin fifteen milliliters of acetone and treated with a solution of 0.5 gram of sodium iodide in five milliliters of acetone. The mixture was heated under reflux with stirring for a period of fifteen minutes, the heat then reduced and the mixture concentrated to onethird volume at reduced pressure. Ice and water were added and the precipitated product collected on filter, washed with water and dried to yield crude 6a-methyl- 9a-flllOIO-l 1B,l7m-dihydroxy-21-iodo-L4 pregnadiene 3 20-dione.

EXAMPLE 18 6a methyl :,21 difluoro 1113,1704 dihydroxy 1,4

pregnadiene 3,20 dione A solution of 0.1 gram of 6a-methyl-9a-fluoro-115,17adihydroxy-21-iodo-1,4-pregnadiene-3,20-dione in fifteen milliliters of acetonitrile was prepared by heating to the boiling point. After cooling to forty degrees centigrade the solution was protected from light and 0.1 milliliter of fifty percent aqueous solution of silver fluoride was added under stirring. Stirring was continued for one hour at about forty degrees centigrade, then another 0.1 milliliter of silver fluoride solution was added and after another hour ofstirring another 0.1 milliliter portion of silver fluoride solution was added. 'Heating and stirring was then continued for a period of two hours. The brownish mixture was thereupon filtered through a bed of Celite diatomaceous' earth and the filtrate was evaporated at reduced pressure from a bath at a temperature of fifty degrees centigrade. The brown residue was thoroughly extracted with three ten-milliliter portions of warm methylene chloride, the extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to approximately eight milliliter volume. The material was then filtered again, evaporated and three times recrystallized from methanol and water to get 60; methyl 9a,2'1 difluoro 115,170 dihydroxy 1,4 pregnadiene 3,20 dione of melting point 262 to 270 degrees centigrade with decomposition.

EXAMPLE 19 6oz methyl 90;,21 difluoro 1113,1704 dihydroxy 1,4 pregnadiene 3,20 dione from 60: methyl 90c fluoro L 115,] 711,21 trihydroxy 41,4 pregnadiene 3,20 dione 2 1 methanesulfona te To a solution of 145 milligrams of 6a methyl 9a 4 fluoro llfi,l7oc,21 trihydroxy 1,4 pregnadiene 3,20 8 dione 21 methanesulfonate in four milliliters of dimethyl sulfoxide was added milligrams of potassium fluoride and the resulting suspension was stirred and heated on the steam bath for a period of sixteen hours. The mixture TABLE II Fraction N0. Solvent Skellysolve B hexanes-aeetone (10%). Skellysolve B hexanes-acetone (12.5%). Skellysolve B hexanes-acetone (15%). Skellysolve B hexanes-aeetone (20%). Acetone.

Fractions 9 through 15 were combined and evaporated to give 54 milligrams of residue. The residue was recrystallized from acetone Skellysolve B hexanes to give 46 milligrams of 6a methyl 9a, 21 difluoro 115,17oa dihydroxy 1,4 pregnadiene 3,20 dione which after 18 additional recrystallization from acetone gave an analytical sample melting at 262 to 274 degrees centigrade with decomposition.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1, A compound selected from the group consisting of 6 methyl 911,21 difluoro 11,19,170; dihydroxy 1,4 pregnadiene 3,20 dione and 6 methyl 901,21 difluoro 17oz hydroxy 1,4 pregnadiene 3,11,20 trione.

2. 60a methyl 901,21 difluoro 113,170; dihydroxy 1,4 pregnadiene 3,20 dione.

3. 6a methyl 9a,21 difluoro 17o: hydroxy 1,4 pregnadiene 3,11,20 trione.

References Cited in the file of this patent Herz et al.: J. A. C. S. 78, September 20, 1956, pages 4812-4814.

Spero et al.: I. A. C. S. 78, December 5, 1956, pages 6213, 6214. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6 - METHYL - 9A,21 - DIFLUORO - 11B,17A - DIHYDROXY - 14PREGNADIENE - 3,20 - DIONE AND 6 - METHYL - 9A,20 - TRIONE. FLUORO - 17A - HYDROXY - 1,4 - PREGNADIENE - 3,11,20 - TRIONE. 